Foregut Microbiome, Gastric Intestinal Metaplasia, and Gastric Cancer Risk Abstract Gastric cancer is a major cancer worldwide. Approximately 1 in 114 men and women will be diagnosed with gastric cancer. Colonization of the stomach by H. pylori is a major risk factor for gastric cancer. However, 99% of people with a history of infection remain asymptomatic and only less than 1% develop gastric cancer. Evidence suggests that H. pylori plays a role in cancer initiation but colonizes gastric precancerous lesions poorly. The loss of H. pylori and impairment of acid secretion in these lesions might facilitate colonization of the stomach by other bacteria that promote gastric carcinogenesis. However, no epidemiologic studies have identified other bacterial factors that may play a role in gastric cancer. Oral health conditions have been related to gastric cancer. Circulating levels of antibodies to oral bacteria have also been related to gastrointestinal cancers, such as orodigestive cancer and pancreatic cancer. These data suggest that the oral microbiome may play a critical role in gastrointestinal maintenance. High-throughput sequencing efforts directed toward sequencing the entire human microbiome have made it possible to comprehensively evaluate specific bacterial taxa that are related to gastric cancer. In this project, we will test the hypothesis that the foregut microbiome influences gastric cancer risk. First, we will use pre-diagnostic oral wash samples and unique resources of the prospective Shanghai Women's Health Study (SWHS), Shanghai Men's Health Study (SMHS), and Southern Community Cohort Study (SCCS)-all with a high seroprevalence of H. pylori (>90% in SWHS and SMHS, and 89% in African Americans and 69% in Caucasians in SCCS)-to conduct the first prospective case-control study of the oral microbiome and gastric cancer, using shotgun metagenomic analyses with 200 gastric cancer cases and 400 controls (Aim 1). Second, using gastric samples from an endoscopic population-based case-control study with 120 cases of gastric intestinal metaplasia and 240 controls, we will associate the composition of the gastric microbiome with gastric intestinal metaplasia, a precancerous lesion at the next-to-last stage of the preneoplastic sequence of gastric cancer (Aim 2). Third, in a separate large prospective case-control study nested in the same SWHS, SMHS, and SCCS with 700 cases and 800 controls, we will then test if antibodies of the newly-identified bacterial markers from Aims 1 and 2 are related to gastric cancer (Aim 3). We will also investigate the interaction between the bacterial markers and different strains of H. pylori in gastric cancer. The proposed study is timely, given the increasing attention on the link between the microbiome and gastrointestinal cancers. These studies will provide complementary and comprehensive data that may be useful to understand the etiology and epidemiology of gastric cancer, as well as to help the development of future interventions and risk stratifications for gastric cancer.